P691: MODELLING OF IMMUNE RESPONSE IN CHRONIC MYELOID LEUKEMIA PATIENTS SUGGESTS POTENTIAL FOR TREATMENT REDUCTION PRIOR TO CESSATION
Authors: E. Karg, C. Baldow, T. Zerjatke, R. E. Clark, I. Roeder, A. C. Fassoni, I. Glauche
Journal: HemaSphere (2022)

Background: Chronic myeloid leukemia (CML) is a malignancy driven by the characteristic BCR-ABL1-fusion oncogene, while the BCR-ABL1 transcript is used as a marker for diagnosis and monitoring. The introduction of tyrosine kinase inhibitors (TKI) marked a substantial progress in CML therapy. Current efforts focus on the discontinuation of TKI therapy for well-responding patients as the long-term drug administration is associated with side effects and high economical costs. Many studies reported that about 50% of patients can achieve sustained treatment free remission (TFR) while 50% present with molecular disease recurrence, typically within two years of stopping. It has been speculated that the immune system (IS) plays a major role in the control of residual disease levels and influences the individual recurrence behaviour. The recently published DESTINY trial (Clark et al., Lancet Haematol, 2019; NCT 01804985) showed that TKI dose reduction prior to cessation can proactively increase the fraction of patients to remain in sustained TFR. However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials. We have previously shown that mathematical models of CML can correctly describe patient time courses after TKI stop (Hahnel et al., Cancer Res, 2020). We classified patients into different groups according to their predicted immune system configuration and showed that one class of patients required complete CML eradication to achieve TFR, while other patients were able to control residual leukemia levels after treatment cessation. While a prospective stratification of the patients is difficult to achievable, we aimed to investigate whether a further optimized dose reduction scheme prior to stopping could further improve TFR. Aims: We aim to use a mathematical description of patient time courses to investigate different TKI dose reductions schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success. Methods: Our analysis is based on a cohort of 72 patients from the DESTINY trial (Clark et al., Lancet Hematol, 2019; NCT 01804985). We applied an established mathematical model (Hahnel et al., Cancer Res, 2020) and obtain individual fits for all patients using a genetic algorithm. Applying a re-sampling approach we derive estimates of recurrence times and fractions for different dose reduction schemes in which the timing and the amount of dose reduction are varied in a systematic manner. Results: We use computer simulations to show that TKI dose reduction prior to treatment cessation appears as an equally efficient approach to achieve high levels of CML patients remaining in TFR compared to full dose treatment for the same duration. Our model simulations confirm clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while at the same time indicating that lower dose TKI treatment is sufficient for many patients. Our model results indicate that a stepwise dose reduction prior to TKI cessation (e.g. 12 month post MR4 at 100% TKI, 12 more months at 50% and 12 more months at 25%) does not limit the overall success rate of TFR, while it substantially reduces the amount of total administered TKI and thereby decreases side effects as well as overall treatment costs. Summary/Conclusion: Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically verifiable strategies that are applicable to many CML patients.